Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities such as reproduction, development and wound repair. Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as “angiogenic diseases”) are caused or exacerbated by unregulated angiogenesis. For example, ocular neovascularization has been implicated as the most common cause of blindness. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (J. Folkman, Cancer Res., 46:467-473 (1986), J. Folkman, J. Natl. Cancer Inst., 82:4-6 (1989)). It has been shown, for example, that tumors which enlarge to greater than 2 mm obtain their own blood supply by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as the liver, lungs, and bones (N. Weidner, et. al., N. Engl. J. Med., 324:1-8 (1991)).
Thrombospondin-1 (TSP-1) is an extracellular matrix protein secreted in response to activation of platelets by thrombin. Various studies have demonstrated that certain peptide analogs of TSP-1 possess antiangiogenesic activity. See, e.g., WO 01/38397, WO 01/38347, WO 99/61476, U.S. Patent Application Pub. No. 2003/0045477, U.S. Patent Application Pub. No. 2002/0183242, U.S. Pat. Nos. 6,774,211, 6,716,963, 6,753,408, and 5,932,545. However, it is desirable to prepare antiangiogenic compounds having improved profiles of activity.